human psychopharmacology Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. Published online 3 January 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2378
Psychomotor and subjective effects of bilastine, hydroxyzine, and cetirizine, in combination with alcohol: a randomized, double-blind, crossover, and positive-controlled and placebo-controlled Phase I clinical trials. Consuelo García-Gea1,2*, Joan Martínez1,2, Maria Rosa Ballester1,2,3, Ignasi Gich1,2,3,4, Román Valiente5 and Rosa Maria Antonijoan1,2,3 1
Centre d’Investigació de Medicaments (CIM), Institut de Investigacions Biomèdiques (IIB), Institut de Recerca (IR); Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain 2 Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain 4 Servei de Epidemiologia Clínica, Barcelona, Spain 5 Departamento de Investigación Clínica FAES FARMA S.A., Vizcaya, Spain
Objective The aim of this study was to compare the effects of concomitant administration of alcohol and bilastine versus alcohol alone on the central nervous system. Methods Twenty-four healthy young volunteers of both sexes participated in a randomized, double-blind, double-dummy, crossover, and positive-controlled and placebo-controlled clinical trials. At 1-week intervals, subjects received six different treatments: (i) placebo; (ii) alcohol 0.8 g/kg alone (ALC); (iii) ALC in combination with: bilastine 20 mg (B20 + A); (iv) bilastine 80 mg (B80 + A); (v) cetirizine 10 mg (CET + A); and (vi) hydroxyzine 25 mg (HYD + A). Psychomotor performance tests (fine motor, finger tapping, nystagmus, critical flicker-fusion frequency, temporal estimation, ‘d2’ cancellation, and simple reaction time) and subjective self-reports (drunkenness, drowsiness, mental slowness, clumsiness, anger, attentiveness, competence, happiness, hostility, interest, and extroversion) were carried out at baseline and multiple points thereafter. Results All active treatments induced a significant psychomotor impairment. The greatest and most lasting impairment was observed with HYD + A followed by B80 + A and CET + A. In contrast, objective measures showed less impairment with B20 + A and ALC, both with a similar magnitude. Self-reports showed a subjective perception of performance impairment in all active treatments. Conclusion Concomitant administration of bilastine (at therapeutic dose) and alcohol does not produce greater central nervous system depressant effects than ACL alone. Copyright © 2014 John Wiley & Sons, Ltd. key words—bilastine; hydroxizyne; cetirizine; alcohol; CNS effects; healthy volunteers
INTRODUCTION Concomitant administration of two or more drugs can produce clinically significant drug interactions (Amstrong and Cozza, 2003). Such interactions are common and cause considerable patient morbidity and mortality. Moreover, these interactions are a major contributor to hospital admissions, treatment failures, avoidable medical complications, and subsequent care costs (Sandson et al., 2005). A drug–alcohol interaction is considered a drug–drug interaction, and many medications
*Correspondence to: C. García-Gea, CIM-Sant Pau, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
have the potential to interact with alcohol, even at moderate drinking levels (Uhart and Wand, 2009). Alcohol and antihistamines are among the most widely used drugs in the world. Newer-generation antihistamines offer an improved central nervous system (CNS) safety profile, although some researchers suggest that certain antihistamines may induce CNS effects at recommended or higher than recommended doses (Shamsi and Hindmarch, 2000). Consequently, mixing alcohol with newer-generation antihistamines can have unpredictable effects and dangers. Bilastine is a new, second-generation antihistamine compound commercially available since February 2012. At the therapeutic dose (20 mg), bilastine has been shown to be clinically effective in patients with seasonal/ Received 6 March 2013 Accepted 11 November 2013
cns effects after alcohol plus bilastine
perennial allergic rhinitis/rhiniconjunctivitis or chronic idiopathic urticaria, with an excellent safety profile (Bachert et al., 2010; Zuberbier et al., 2010). A previous phase I clinical study carried out in our unit showed a potent peripheral anti-H1 activity after single and repeated administration of bilastine at doses of 20 mg, 40 mg, and 80 mg. Moreover, in that study, psychomotor impairment was observed only at the highest evaluated dose (García-Gea et al., 2008). Recently, a double-blind, crossover, and placebocontrolled study was carried out to assess the effects of two different doses of bilastine (20 mg and 40 mg) on driving ability after single and repeated administration (Conen et al., 2011). The authors of that study concluded that bilastine did not impair driving after single or repeated doses, and can thus be used safely in traffic at doses up to 40 mg. Although multiple studies report that non-sedating antihistamines do not potentiate the adverse CNS effects of alcohol (Vermeeren et al., 2002; Barbanoj et al., 2006), this lack of interaction with alcohol must be established experimentally for each new antihistamine. The main objective of the study presented here was to assess whether concomitant alcohol and bilastine (20 mg and 80 mg) induces more CNS depressant effects than those produced by alcohol alone. METHODS Ethics The clinical trial was approved by the Hospital Research Ethics Committee at the study center and the Spanish Drug Agency and was conducted in accordance with the principles stated in the Declaration of Helsinki and Good Clinical Practice guidelines. All volunteers gave written informed consent before the start of the clinical trial and were paid for their participation. Study population The study population consisted of 24 healthy young male and female adults ranging in age from 18 to 40 years. Participants were chosen from the database of volunteers at the Centre d’Investigació de Medicaments (CIM-Sant Pau. IIB-Sant Pau [Institut de Recerca], Hospital de la Santa Creu i Sant Pau [HSCSP], Barcelona, Spain). All volunteers enrolled were rigorously screened to ensure strict compliance with the inclusion/exclusion criteria. The subjects underwent a medical interview and physical examination no more than 21 days before study initiation. Exclusion criteria included any history of medical or psychiatric illness, or null/abusive alcohol consumption (for inclusion, the limits were Copyright © 2014 John Wiley & Sons, Ltd.
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21–60 g/day of alcohol for men and 21–40 g/day for women). All subjects were evaluated for their capacity to understand and correctly perform the objective psychomotor tests used to evaluate CNS effects. During the week prior to the first experimental session, the subjects were trained in how to perform the psychomotor tests (12 practice sessions for each test). No alcohol or coffee was allowed in the 48 h before or after each treatment session. Participants were requested not to take any medications during the study and to keep regular sleep-wake habits. Study experimental procedures The clinical trial was conducted according to a randomized, double-blind, double-dummy, crossover, positivecontrolled, and placebo-controlled design. It consisted of six experimental sessions separated by a minimum washout period of 7 days. Prior to each experimental session, all subjects underwent urine drug screening and female subjects also underwent a urine pregnancy test. Subjects were admitted to the treatment unit the night prior to the scheduled experimental session and were not discharged until +11-h post-medication. The following drug combinations were administered in a balanced and randomized manner: (i) placebo + alcohol placebo (PLA); (ii) placebo + alcohol 0.8 g/kg (ALC); (iii) bilastine 20 mg + alcohol 0.8 g/kg (B20 + A); (iv) bilastine 80 mg + alcohol 0.8 g/kg (B80 + A); (v) cetirizine 10 mg + alcohol 0.8 g/kg (CET + A); and (vi) hydroxyzine 25 mg + alcohol 0.8 g/kg (HYD + A). The study medication was administered in the early morning under fasting conditions together with an orangeflavored beverage. Fasting continued until +3-h postmedication at which time a standard breakfast was served, followed by a standard lunch at +7-h postmedication. Water intake was allowed “ad libitum” from +2-h post-medication. Double-dummy techniques were used to achieve double-blind conditions. In each experimental session, subjects took four capsules (all with the same external appearance) and drank the same volume of drink (400 ml containing ethanol at dose of 0.8 g/Kg). Drinks were prepared by a trained technician not otherwise involved in the experimental procedures. Drink preparation was carried out immediately prior to intake. Alcohol dosing was individually adjusted to body weight, which was measured in the early morning of each experimental session. This was expressed in ml of the alcoholic beverage (vodka; 40% alcohol) using the following calculations: (i) grams of alcohol = weight × 0.8); (ii) milliliters of alcohol = grams of alcohol/alcohol density; and (iii) milliliters of vodka = ml of alcohol × (100/40). Next, the resultant volume of vodka was Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
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diluted in water to obtain a total volume of 200 ml, then orange-flavored beverage juice was added to reach a total final volume of 400 ml. For the alcohol-free drink, vodka was replaced by water. The final volume was distributed equally in six glasses that were covered with aluminium foil through which a straw was inserted allowing intake; thus, the contents of the glass remained covered. The drink content was masked by adding 2 ml of supernatant alcohol to the aluminium foil. Subjects were allowed 30 min to consume the six glasses (one glass every 5 min). Subjects were instructed to take beverages as homogeneous as possible over the 30-min period. In all cases, the study medication was added to the first glass. Pharmacodynamic assessments (objective psychomotor performance tests and subjective reports on mood) were undertaken at baseline and at +1-h, +2-h, +4-h, +6-h, +8-h, and +10-h post-administration. Clinical safety was assessed by continuous recording of adverse events and daily recording of vital signs. Laboratory tests and electrocardiogram recordings were taken at +24-h post-medication. In addition, subjects underwent a complete physical examination at the end of the study. Psychomotor performance tests A comprehensive battery of seven psychomotor performance tests (PPTs) was administered to evaluate objective CNS effects, as follows: motor activity, perception, attention, and associative skills. The tests are described in the succeeding text. Motor activity was assessed by three separate tests, as follows: the fine motor test (FMT), the finger tapping test (FTT), and the nystagmus test (NYS). The FMT measures subject’s ability to perform quick and precise movements that require good hand–eye coordination. In the FMT test, two rectangles (one for each hand) measuring 10 cm × 5 cm and divided into smaller rectangles were shown on the test page. Subjects were asked to draw a point in the center of the smaller squares as fast as possible. The total number (FMT_tt) of squares marked and the number of squares dotted correctly (FMT_co) in a 30-s period were evaluated. The FTT measures ability to perform fast wrist and finger movements. Subjects were asked to use their dominant hand to tap a pen against a metal plate as fast as possible. The primary parameter evaluated was the mean number of taps/second in a 30-s period (FTT_tt). NYS measures the extent of a sudden characteristic spasmodic movement of the eye at the start and the end of a rotation period. Subjects were told to focus on and track a target object (a pen) with their eyes. The pen was located at a distance of 50 cm directly in front of the subject. A trained technician moved Copyright © 2014 John Wiley & Sons, Ltd.
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the pen until he perceived that the subject’s eyes began to jerk (nystagmus). The primary parameter evaluated was the mean degree at which nystagmus occurred (NYS_gr). Two tests were used to assess perception: the critical flicker-fusion frequency test (CFF) and the temporal estimation test (TET). The CFF is an indicator of cortical arousal and it measures CNS information processing speed. In this task, subjects were exposed to successive cycles of increasing and decreasing flickering frequencies (from 25 to 60 Hz) of a 2 mm red light. Subjects were required to indicate when they perceived a change from flickering to constant light (fusion frequency) and from constant to flickering light (flicker frequency). The primary parameter was the mean threshold of flicker-fusion frequency (CFF_th) in four up and down trials. The TET measures the subjective perception of time. Subjects were exposed to an acoustic signal and asked to press a key when they estimated that 15 s had passed. Five trials were performed and the primary parameter evaluated in this test was the mean estimated time from the five trials (TET_tt). Attention was assessed using the “d2” Cancellation Test (D2T), which measures attention and recognition of sensory information. The test items were listed on two separate pages, each with 14 lines. These items consisted of the letters d or p with one to four dashes located (individually or in pairs) above or below the letter. Subjects were requested to cross out all instances of the letter d containing two dashes (either 2 above, 2 below or 1 above and 1 below). The total number of responses (D2T_tt) and the number of correct responses (D2T_co) in a 280-s period were evaluated. Associative skills were assessed with the simple reaction time test (SRT), which measures the speed of the subjects’ motor response to a simple sensory cue. Thirty visual stimuli (yellow lights) were randomly shown on a screen at intervals of 2.5 to 6.5 s. Subjects were told to keep their finger on the “rest button” (shown on the screen) until a yellow light appeared, at which time they were to press the “reaction button” (also on the screen) as quickly as possible. After pressing the reaction button, subjects were instructed to immediately return their finger to the “rest button” until the next stimulus was shown. The primary parameter evaluated was the mean reaction time (SRT_rt), defined as the time elapsed between stimulus presentation and release of the “rest button”. A secondary parameter, motor time (SRT_mt), was also evaluated. Motor time was defined as the time elapsed between releasing of the “rest button” and pressing the “reaction button”. Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
cns effects after alcohol plus bilastine
The microcomputer-based Vienna test system (SCHUFRIED GmbH, Mödling, Austria) was used to conduct some of the tests (FTT, CFF, and SRT), whereas other tests were performed with specially-designed evaluation instruments (NYS and TET). Two of the tests (FMT and D2T) were pen-and-paper-based tests. The validity, reliability, and pharmacosensitivity of the psychomotor tests to assess the effects of the CNS drugs is well-documented (Parrot, 1991; Hindmarch, 2004; Wezenberg et al., 2007). The use of a battery of psychomotor laboratory tests is a common method in psychopharmacology research, particularly in the early stages of drug development. Such tests allow researchers to evaluate a variety of skills and abilities involved in daily human functioning. Moreover, no complex equipment is usually required, and the tests are easy to conduct, relatively inexpensive, and repeated testing can be carried out under controlled standardized conditions. We selected the battery of tests based on our previous experience performing similar studies (Barbanoj et al., 2004, 2006; García-Gea et al., 2008, 2010). In addition, these tests enable us to evaluate psychomotor performance in standardized conditions with little interference from other factors, such as interindividual or cultural differences. Also, because these tests have a short duration (approximately 15 min), it was possible to take repeated measures without any fatigue-related interference on performance. Subjective self-reports on mood To evaluate subjective CNS effects, we used 11 visual analogue scales (VAS). These scales consisted of ungraded horizontal lines (100 mm in length) with opposite adjectives (i.e., antonyms) placed at each extreme. The adjectives pairs, all of which are related to a single subjective feeling, included the following: sober/drunk, awake/drowsy, mentally slow/quick-witted, well-coordinated/clumsy, glad/angry, attentive/dreamy, incompetent/proficient, happy/sad, hostile/kind, interested/ bored, and introverted/extraverted. Subjects were requested to rate their current state by marking a vertical line on the scale for each item (feeling). Responses from the previous evaluations were not visible to the volunteers. To quantify the response, the subjects’ answers were measured to the nearest millimeter. In this way, scores (in millimeters) were computed for drunkenness (VAS_dk), drowsiness (VAS_dw), mental slowness (VAS_ms), clumsiness (VAS_cl), anger (VAS_an), attentiveness (VAS_at), competence (VAS_co), happiness (VAS_ha), hostility (VAS_ho), interest (VAS_in), and extroversion (VAS_ex). Although VAS has been long been known to be an effective tool to measure changes over time in response to drug treatment, some authors question the reliability and validity of the associated measurement variables Copyright © 2014 John Wiley & Sons, Ltd.
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(Jensen et al., 2003; Vautier, 2011). Nevertheless, in phase I clinical trials, VAS continues to be the most widely used tool to assess the subjective impact of drugs because of its many advantages: VAS is easy for subjects to understand, can be completed and scored quickly, does not require the subject to be highlymotivated, and allows for numerous measures of multiple feelings in a short period. Evaluation of tolerability Clinical tolerability and safety were assessed by recording adverse events (AEs) and vital signs (supine systolic and diastolic blood pressures, and heart rate) on a daily basis. Blood tests (haematology and biochemistry) and electrocardiogram were performed at the end of each experimental session. At the end of the study, a complete physical examination was also performed. Statistics Parametric univariate analysis (each variable evaluated independently) was based on the comparison of baseline performance and single-treatment effects. A preliminary three-way analysis of variance (ANOVA) was carried out to evaluate possible sex-related differences. This analysis included the treatments, test-response times, and sex as main effects. According to the results obtained for the factor treatment by time by gender interaction, the gender was included or not in the subsequent statistical analyses. Basal performance was compared by applying one-way (treatment factor) or two-way (treatment and gender factors) ANOVAs. Treatment effects were evaluated by means of twoway (treatment and time factors) or three-way (treatment, time, and gender factors) ANOVAs. In the evaluation of treatments effects, data were expressed as differences from baseline scores. In the assessment of time effects and the interaction treatment by time or the interaction treatment by time by gender, raw data were analysed. When suitable, descriptive pairwise comparisons were performed using the paired t-test, without adjusting for multiple testing. A multivariate, non-parametric analysis was also applied to obtain an overall view of the results. The relation between treatment and effects (anlysed separately for objective and subjective variables) were evaluated by means of Friedma’s rank ANOVA and Wilcoxon– Wilcox tests of changes from baseline values. Transformations were applied so that a lower Friedman’s rank indicated greater cognitive impairment or subjective impact. In the objective variables, the impairment was defined as decreases in FMT_co, FMT_tt, FTT_tt, NYS_gr, CFF_th, D2T_co, or D2T_tt and as increases in TET_tt, SRT_rt, or SRT_mt. In the subjective Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
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variables, a higher subjective impact was defined as increases in VAS_dk, VAS_dw, VAS_an, VAS_ho, or VAS_ex and decreases in VAS_ms, VAS_cl, VAS_at, VAS_co, VAS_ha, or VAS_in. Statistical analyses were performed using the SPSS version 19.0 software program (SPSS Inc, Chicago, Ill.). ANOVAS were assessed with a generalized linear model approach. The Greenhouse–Geisser correction was used in the analysis. Differences were considered significant when the probability of a type I error was less than 0.05. No corrections for multiple comparisons were applied. Safety and tolerability parameters were evaluated in terms of “clinically relevant changes”. RESULTS Study population A total of 43 volunteers (22 men and 21 women) were screened. Of these, 16 volunteers (6 men and 10 women) were dropped for medical reasons (seven subjects), lack of regular alcohol consumption (two subjects), use of
ET AL.
restricted medications (two subjects), and personal reasons (five subjects). Of the 27 remaining subjects, 24 (15 men and 9 women) were included in the study and were randomised to treatment, whereas the remaining three subjects (1 man and 2 women) were kept as reserve volunteers. All randomise volunteers completed the entire study. The mean (SD) demographic characteristics of the study sample were as follows: age, 25.9 years (4.82 years); weight, 69.1 kg (9.21 kg); height, 171.2 cm (8.84 cm), and Quetelet index, 23.5 (2.05). All subjects who completed the trial were compliant with the study protocol. Analysis of gender effect The three-way ANOVAs applied showed no significant differences for the factor “treatment by time by gender interaction” in any variables obtained in the PPT and VAS evaluations (Table 1). Therefore, gender was not included in the subsequent statistical analyses. Analysis of baseline conditions Basal scores for both PPT and VAS did not differ significantly between experimental sessions, indicating
Table 1. Statistical results (p-values) from univariate analysis for gender effects, for baseline conditions between treatment conditions, for treatment effects, and for time and treatment by time effects (24 healthy subjects)
FMT_co (number) FMT_tt (number) FTT_tt (number) NYS_gr (degree) CFF_th (Hz) TET_tt (seconds) D2T_co (number) D2T_tt (number) SRT_rt (miliseconds) SRT_mt (miliseconds) VAS_dk (mm) VAS_dw (mm) VAS_ms (mm) VAS_cl (mm) VAS_an (mm) VAS_at (mm) VAS_co (mm) VAS_ha (mm) VAS_ho (mm) VAS_in (mm) VAS_ex (mm)
Gendera
Baselineb
Treatmentc
Timec
Tr x Tic
0.547 0.396 0.201 0.250 0.241 0.641 0.086 0.160 0.285 0.398 0.515 0.356 0.505 0.712 0.658 0.378 0.176 0.824 0.503 0.526 0.391
0.082 0.974 0.462 0.480 0.902 0.053 0.467 0.507 0.704 0.685 0.395 0.504 0.389 0.585 0.892 0.712 0.612 0.736 0.348 0.320 0.521
0.027 0.261
Psychomotor and subjective effects of bilastine, hydroxyzine, and cetirizine, in combination with alcohol: a randomized, double-blind, crossover, and positive-controlled and placebo-controlled Phase I clinical trials. Consuelo García-Gea1,2*, Joan Martínez1,2, Maria Rosa Ballester1,2,3, Ignasi Gich1,2,3,4, Román Valiente5 and Rosa Maria Antonijoan1,2,3 1
Centre d’Investigació de Medicaments (CIM), Institut de Investigacions Biomèdiques (IIB), Institut de Recerca (IR); Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain 2 Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain 4 Servei de Epidemiologia Clínica, Barcelona, Spain 5 Departamento de Investigación Clínica FAES FARMA S.A., Vizcaya, Spain
Objective The aim of this study was to compare the effects of concomitant administration of alcohol and bilastine versus alcohol alone on the central nervous system. Methods Twenty-four healthy young volunteers of both sexes participated in a randomized, double-blind, double-dummy, crossover, and positive-controlled and placebo-controlled clinical trials. At 1-week intervals, subjects received six different treatments: (i) placebo; (ii) alcohol 0.8 g/kg alone (ALC); (iii) ALC in combination with: bilastine 20 mg (B20 + A); (iv) bilastine 80 mg (B80 + A); (v) cetirizine 10 mg (CET + A); and (vi) hydroxyzine 25 mg (HYD + A). Psychomotor performance tests (fine motor, finger tapping, nystagmus, critical flicker-fusion frequency, temporal estimation, ‘d2’ cancellation, and simple reaction time) and subjective self-reports (drunkenness, drowsiness, mental slowness, clumsiness, anger, attentiveness, competence, happiness, hostility, interest, and extroversion) were carried out at baseline and multiple points thereafter. Results All active treatments induced a significant psychomotor impairment. The greatest and most lasting impairment was observed with HYD + A followed by B80 + A and CET + A. In contrast, objective measures showed less impairment with B20 + A and ALC, both with a similar magnitude. Self-reports showed a subjective perception of performance impairment in all active treatments. Conclusion Concomitant administration of bilastine (at therapeutic dose) and alcohol does not produce greater central nervous system depressant effects than ACL alone. Copyright © 2014 John Wiley & Sons, Ltd. key words—bilastine; hydroxizyne; cetirizine; alcohol; CNS effects; healthy volunteers
INTRODUCTION Concomitant administration of two or more drugs can produce clinically significant drug interactions (Amstrong and Cozza, 2003). Such interactions are common and cause considerable patient morbidity and mortality. Moreover, these interactions are a major contributor to hospital admissions, treatment failures, avoidable medical complications, and subsequent care costs (Sandson et al., 2005). A drug–alcohol interaction is considered a drug–drug interaction, and many medications
*Correspondence to: C. García-Gea, CIM-Sant Pau, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
have the potential to interact with alcohol, even at moderate drinking levels (Uhart and Wand, 2009). Alcohol and antihistamines are among the most widely used drugs in the world. Newer-generation antihistamines offer an improved central nervous system (CNS) safety profile, although some researchers suggest that certain antihistamines may induce CNS effects at recommended or higher than recommended doses (Shamsi and Hindmarch, 2000). Consequently, mixing alcohol with newer-generation antihistamines can have unpredictable effects and dangers. Bilastine is a new, second-generation antihistamine compound commercially available since February 2012. At the therapeutic dose (20 mg), bilastine has been shown to be clinically effective in patients with seasonal/ Received 6 March 2013 Accepted 11 November 2013
cns effects after alcohol plus bilastine
perennial allergic rhinitis/rhiniconjunctivitis or chronic idiopathic urticaria, with an excellent safety profile (Bachert et al., 2010; Zuberbier et al., 2010). A previous phase I clinical study carried out in our unit showed a potent peripheral anti-H1 activity after single and repeated administration of bilastine at doses of 20 mg, 40 mg, and 80 mg. Moreover, in that study, psychomotor impairment was observed only at the highest evaluated dose (García-Gea et al., 2008). Recently, a double-blind, crossover, and placebocontrolled study was carried out to assess the effects of two different doses of bilastine (20 mg and 40 mg) on driving ability after single and repeated administration (Conen et al., 2011). The authors of that study concluded that bilastine did not impair driving after single or repeated doses, and can thus be used safely in traffic at doses up to 40 mg. Although multiple studies report that non-sedating antihistamines do not potentiate the adverse CNS effects of alcohol (Vermeeren et al., 2002; Barbanoj et al., 2006), this lack of interaction with alcohol must be established experimentally for each new antihistamine. The main objective of the study presented here was to assess whether concomitant alcohol and bilastine (20 mg and 80 mg) induces more CNS depressant effects than those produced by alcohol alone. METHODS Ethics The clinical trial was approved by the Hospital Research Ethics Committee at the study center and the Spanish Drug Agency and was conducted in accordance with the principles stated in the Declaration of Helsinki and Good Clinical Practice guidelines. All volunteers gave written informed consent before the start of the clinical trial and were paid for their participation. Study population The study population consisted of 24 healthy young male and female adults ranging in age from 18 to 40 years. Participants were chosen from the database of volunteers at the Centre d’Investigació de Medicaments (CIM-Sant Pau. IIB-Sant Pau [Institut de Recerca], Hospital de la Santa Creu i Sant Pau [HSCSP], Barcelona, Spain). All volunteers enrolled were rigorously screened to ensure strict compliance with the inclusion/exclusion criteria. The subjects underwent a medical interview and physical examination no more than 21 days before study initiation. Exclusion criteria included any history of medical or psychiatric illness, or null/abusive alcohol consumption (for inclusion, the limits were Copyright © 2014 John Wiley & Sons, Ltd.
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21–60 g/day of alcohol for men and 21–40 g/day for women). All subjects were evaluated for their capacity to understand and correctly perform the objective psychomotor tests used to evaluate CNS effects. During the week prior to the first experimental session, the subjects were trained in how to perform the psychomotor tests (12 practice sessions for each test). No alcohol or coffee was allowed in the 48 h before or after each treatment session. Participants were requested not to take any medications during the study and to keep regular sleep-wake habits. Study experimental procedures The clinical trial was conducted according to a randomized, double-blind, double-dummy, crossover, positivecontrolled, and placebo-controlled design. It consisted of six experimental sessions separated by a minimum washout period of 7 days. Prior to each experimental session, all subjects underwent urine drug screening and female subjects also underwent a urine pregnancy test. Subjects were admitted to the treatment unit the night prior to the scheduled experimental session and were not discharged until +11-h post-medication. The following drug combinations were administered in a balanced and randomized manner: (i) placebo + alcohol placebo (PLA); (ii) placebo + alcohol 0.8 g/kg (ALC); (iii) bilastine 20 mg + alcohol 0.8 g/kg (B20 + A); (iv) bilastine 80 mg + alcohol 0.8 g/kg (B80 + A); (v) cetirizine 10 mg + alcohol 0.8 g/kg (CET + A); and (vi) hydroxyzine 25 mg + alcohol 0.8 g/kg (HYD + A). The study medication was administered in the early morning under fasting conditions together with an orangeflavored beverage. Fasting continued until +3-h postmedication at which time a standard breakfast was served, followed by a standard lunch at +7-h postmedication. Water intake was allowed “ad libitum” from +2-h post-medication. Double-dummy techniques were used to achieve double-blind conditions. In each experimental session, subjects took four capsules (all with the same external appearance) and drank the same volume of drink (400 ml containing ethanol at dose of 0.8 g/Kg). Drinks were prepared by a trained technician not otherwise involved in the experimental procedures. Drink preparation was carried out immediately prior to intake. Alcohol dosing was individually adjusted to body weight, which was measured in the early morning of each experimental session. This was expressed in ml of the alcoholic beverage (vodka; 40% alcohol) using the following calculations: (i) grams of alcohol = weight × 0.8); (ii) milliliters of alcohol = grams of alcohol/alcohol density; and (iii) milliliters of vodka = ml of alcohol × (100/40). Next, the resultant volume of vodka was Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
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diluted in water to obtain a total volume of 200 ml, then orange-flavored beverage juice was added to reach a total final volume of 400 ml. For the alcohol-free drink, vodka was replaced by water. The final volume was distributed equally in six glasses that were covered with aluminium foil through which a straw was inserted allowing intake; thus, the contents of the glass remained covered. The drink content was masked by adding 2 ml of supernatant alcohol to the aluminium foil. Subjects were allowed 30 min to consume the six glasses (one glass every 5 min). Subjects were instructed to take beverages as homogeneous as possible over the 30-min period. In all cases, the study medication was added to the first glass. Pharmacodynamic assessments (objective psychomotor performance tests and subjective reports on mood) were undertaken at baseline and at +1-h, +2-h, +4-h, +6-h, +8-h, and +10-h post-administration. Clinical safety was assessed by continuous recording of adverse events and daily recording of vital signs. Laboratory tests and electrocardiogram recordings were taken at +24-h post-medication. In addition, subjects underwent a complete physical examination at the end of the study. Psychomotor performance tests A comprehensive battery of seven psychomotor performance tests (PPTs) was administered to evaluate objective CNS effects, as follows: motor activity, perception, attention, and associative skills. The tests are described in the succeeding text. Motor activity was assessed by three separate tests, as follows: the fine motor test (FMT), the finger tapping test (FTT), and the nystagmus test (NYS). The FMT measures subject’s ability to perform quick and precise movements that require good hand–eye coordination. In the FMT test, two rectangles (one for each hand) measuring 10 cm × 5 cm and divided into smaller rectangles were shown on the test page. Subjects were asked to draw a point in the center of the smaller squares as fast as possible. The total number (FMT_tt) of squares marked and the number of squares dotted correctly (FMT_co) in a 30-s period were evaluated. The FTT measures ability to perform fast wrist and finger movements. Subjects were asked to use their dominant hand to tap a pen against a metal plate as fast as possible. The primary parameter evaluated was the mean number of taps/second in a 30-s period (FTT_tt). NYS measures the extent of a sudden characteristic spasmodic movement of the eye at the start and the end of a rotation period. Subjects were told to focus on and track a target object (a pen) with their eyes. The pen was located at a distance of 50 cm directly in front of the subject. A trained technician moved Copyright © 2014 John Wiley & Sons, Ltd.
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the pen until he perceived that the subject’s eyes began to jerk (nystagmus). The primary parameter evaluated was the mean degree at which nystagmus occurred (NYS_gr). Two tests were used to assess perception: the critical flicker-fusion frequency test (CFF) and the temporal estimation test (TET). The CFF is an indicator of cortical arousal and it measures CNS information processing speed. In this task, subjects were exposed to successive cycles of increasing and decreasing flickering frequencies (from 25 to 60 Hz) of a 2 mm red light. Subjects were required to indicate when they perceived a change from flickering to constant light (fusion frequency) and from constant to flickering light (flicker frequency). The primary parameter was the mean threshold of flicker-fusion frequency (CFF_th) in four up and down trials. The TET measures the subjective perception of time. Subjects were exposed to an acoustic signal and asked to press a key when they estimated that 15 s had passed. Five trials were performed and the primary parameter evaluated in this test was the mean estimated time from the five trials (TET_tt). Attention was assessed using the “d2” Cancellation Test (D2T), which measures attention and recognition of sensory information. The test items were listed on two separate pages, each with 14 lines. These items consisted of the letters d or p with one to four dashes located (individually or in pairs) above or below the letter. Subjects were requested to cross out all instances of the letter d containing two dashes (either 2 above, 2 below or 1 above and 1 below). The total number of responses (D2T_tt) and the number of correct responses (D2T_co) in a 280-s period were evaluated. Associative skills were assessed with the simple reaction time test (SRT), which measures the speed of the subjects’ motor response to a simple sensory cue. Thirty visual stimuli (yellow lights) were randomly shown on a screen at intervals of 2.5 to 6.5 s. Subjects were told to keep their finger on the “rest button” (shown on the screen) until a yellow light appeared, at which time they were to press the “reaction button” (also on the screen) as quickly as possible. After pressing the reaction button, subjects were instructed to immediately return their finger to the “rest button” until the next stimulus was shown. The primary parameter evaluated was the mean reaction time (SRT_rt), defined as the time elapsed between stimulus presentation and release of the “rest button”. A secondary parameter, motor time (SRT_mt), was also evaluated. Motor time was defined as the time elapsed between releasing of the “rest button” and pressing the “reaction button”. Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
cns effects after alcohol plus bilastine
The microcomputer-based Vienna test system (SCHUFRIED GmbH, Mödling, Austria) was used to conduct some of the tests (FTT, CFF, and SRT), whereas other tests were performed with specially-designed evaluation instruments (NYS and TET). Two of the tests (FMT and D2T) were pen-and-paper-based tests. The validity, reliability, and pharmacosensitivity of the psychomotor tests to assess the effects of the CNS drugs is well-documented (Parrot, 1991; Hindmarch, 2004; Wezenberg et al., 2007). The use of a battery of psychomotor laboratory tests is a common method in psychopharmacology research, particularly in the early stages of drug development. Such tests allow researchers to evaluate a variety of skills and abilities involved in daily human functioning. Moreover, no complex equipment is usually required, and the tests are easy to conduct, relatively inexpensive, and repeated testing can be carried out under controlled standardized conditions. We selected the battery of tests based on our previous experience performing similar studies (Barbanoj et al., 2004, 2006; García-Gea et al., 2008, 2010). In addition, these tests enable us to evaluate psychomotor performance in standardized conditions with little interference from other factors, such as interindividual or cultural differences. Also, because these tests have a short duration (approximately 15 min), it was possible to take repeated measures without any fatigue-related interference on performance. Subjective self-reports on mood To evaluate subjective CNS effects, we used 11 visual analogue scales (VAS). These scales consisted of ungraded horizontal lines (100 mm in length) with opposite adjectives (i.e., antonyms) placed at each extreme. The adjectives pairs, all of which are related to a single subjective feeling, included the following: sober/drunk, awake/drowsy, mentally slow/quick-witted, well-coordinated/clumsy, glad/angry, attentive/dreamy, incompetent/proficient, happy/sad, hostile/kind, interested/ bored, and introverted/extraverted. Subjects were requested to rate their current state by marking a vertical line on the scale for each item (feeling). Responses from the previous evaluations were not visible to the volunteers. To quantify the response, the subjects’ answers were measured to the nearest millimeter. In this way, scores (in millimeters) were computed for drunkenness (VAS_dk), drowsiness (VAS_dw), mental slowness (VAS_ms), clumsiness (VAS_cl), anger (VAS_an), attentiveness (VAS_at), competence (VAS_co), happiness (VAS_ha), hostility (VAS_ho), interest (VAS_in), and extroversion (VAS_ex). Although VAS has been long been known to be an effective tool to measure changes over time in response to drug treatment, some authors question the reliability and validity of the associated measurement variables Copyright © 2014 John Wiley & Sons, Ltd.
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(Jensen et al., 2003; Vautier, 2011). Nevertheless, in phase I clinical trials, VAS continues to be the most widely used tool to assess the subjective impact of drugs because of its many advantages: VAS is easy for subjects to understand, can be completed and scored quickly, does not require the subject to be highlymotivated, and allows for numerous measures of multiple feelings in a short period. Evaluation of tolerability Clinical tolerability and safety were assessed by recording adverse events (AEs) and vital signs (supine systolic and diastolic blood pressures, and heart rate) on a daily basis. Blood tests (haematology and biochemistry) and electrocardiogram were performed at the end of each experimental session. At the end of the study, a complete physical examination was also performed. Statistics Parametric univariate analysis (each variable evaluated independently) was based on the comparison of baseline performance and single-treatment effects. A preliminary three-way analysis of variance (ANOVA) was carried out to evaluate possible sex-related differences. This analysis included the treatments, test-response times, and sex as main effects. According to the results obtained for the factor treatment by time by gender interaction, the gender was included or not in the subsequent statistical analyses. Basal performance was compared by applying one-way (treatment factor) or two-way (treatment and gender factors) ANOVAs. Treatment effects were evaluated by means of twoway (treatment and time factors) or three-way (treatment, time, and gender factors) ANOVAs. In the evaluation of treatments effects, data were expressed as differences from baseline scores. In the assessment of time effects and the interaction treatment by time or the interaction treatment by time by gender, raw data were analysed. When suitable, descriptive pairwise comparisons were performed using the paired t-test, without adjusting for multiple testing. A multivariate, non-parametric analysis was also applied to obtain an overall view of the results. The relation between treatment and effects (anlysed separately for objective and subjective variables) were evaluated by means of Friedma’s rank ANOVA and Wilcoxon– Wilcox tests of changes from baseline values. Transformations were applied so that a lower Friedman’s rank indicated greater cognitive impairment or subjective impact. In the objective variables, the impairment was defined as decreases in FMT_co, FMT_tt, FTT_tt, NYS_gr, CFF_th, D2T_co, or D2T_tt and as increases in TET_tt, SRT_rt, or SRT_mt. In the subjective Hum. Psychopharmacol Clin Exp 2014; 29: 120–132. DOI: 10.1002/hup
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variables, a higher subjective impact was defined as increases in VAS_dk, VAS_dw, VAS_an, VAS_ho, or VAS_ex and decreases in VAS_ms, VAS_cl, VAS_at, VAS_co, VAS_ha, or VAS_in. Statistical analyses were performed using the SPSS version 19.0 software program (SPSS Inc, Chicago, Ill.). ANOVAS were assessed with a generalized linear model approach. The Greenhouse–Geisser correction was used in the analysis. Differences were considered significant when the probability of a type I error was less than 0.05. No corrections for multiple comparisons were applied. Safety and tolerability parameters were evaluated in terms of “clinically relevant changes”. RESULTS Study population A total of 43 volunteers (22 men and 21 women) were screened. Of these, 16 volunteers (6 men and 10 women) were dropped for medical reasons (seven subjects), lack of regular alcohol consumption (two subjects), use of
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restricted medications (two subjects), and personal reasons (five subjects). Of the 27 remaining subjects, 24 (15 men and 9 women) were included in the study and were randomised to treatment, whereas the remaining three subjects (1 man and 2 women) were kept as reserve volunteers. All randomise volunteers completed the entire study. The mean (SD) demographic characteristics of the study sample were as follows: age, 25.9 years (4.82 years); weight, 69.1 kg (9.21 kg); height, 171.2 cm (8.84 cm), and Quetelet index, 23.5 (2.05). All subjects who completed the trial were compliant with the study protocol. Analysis of gender effect The three-way ANOVAs applied showed no significant differences for the factor “treatment by time by gender interaction” in any variables obtained in the PPT and VAS evaluations (Table 1). Therefore, gender was not included in the subsequent statistical analyses. Analysis of baseline conditions Basal scores for both PPT and VAS did not differ significantly between experimental sessions, indicating
Table 1. Statistical results (p-values) from univariate analysis for gender effects, for baseline conditions between treatment conditions, for treatment effects, and for time and treatment by time effects (24 healthy subjects)
FMT_co (number) FMT_tt (number) FTT_tt (number) NYS_gr (degree) CFF_th (Hz) TET_tt (seconds) D2T_co (number) D2T_tt (number) SRT_rt (miliseconds) SRT_mt (miliseconds) VAS_dk (mm) VAS_dw (mm) VAS_ms (mm) VAS_cl (mm) VAS_an (mm) VAS_at (mm) VAS_co (mm) VAS_ha (mm) VAS_ho (mm) VAS_in (mm) VAS_ex (mm)
Gendera
Baselineb
Treatmentc
Timec
Tr x Tic
0.547 0.396 0.201 0.250 0.241 0.641 0.086 0.160 0.285 0.398 0.515 0.356 0.505 0.712 0.658 0.378 0.176 0.824 0.503 0.526 0.391
0.082 0.974 0.462 0.480 0.902 0.053 0.467 0.507 0.704 0.685 0.395 0.504 0.389 0.585 0.892 0.712 0.612 0.736 0.348 0.320 0.521
0.027 0.261
